Differences in Immunological Landscape between EGFR-Mutated and Wild-Type Lung Adenocarcinoma.

Jia-Wei Luo,Jia-Lu Wang,Xue-Fei Li,Feng-Ying Wu,Cai-Cun Zhou,Xue-Cheng Sun,Yan-Hua Guo,Laura Bergantini

doi:10.1155/2021/3776854

Abstract

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients (P = 0.0065). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

Highlights

Immunotherapy targeting programmed cell death 1 (PD1) or its ligand, PD1 ligand 1 (PD-L1), has transformed the paradigm of lung cancer treatment
The PD-L1 expression level, tumor mutation burden (TMB), and infiltrated lymphocyte have been identified as predictive markers for anti-PD1/PD-L1 immunotherapy [9]
A total of 323 eligible patients were enrolled based on the following inclusion criteria: (i) they are pathologically diagnosed with lung adenocarcinoma, (ii) the pathological stage was IA to IIIA, (iii) the content of tumor tissue components can be observed on HEstained sections ≥ 20%, and (iv) patient’s clinical data was complete

Summary

Introduction

Immunotherapy targeting programmed cell death 1 (PD1) or its ligand, PD1 ligand 1 (PD-L1), has transformed the paradigm of lung cancer treatment. Durable clinical benefit was observed in advanced lung cancer patients treated with PD1/PD-L1 inhibitors [1, 2]. Anti-PD1/PD-L1 treatment has been approved as a second-line or first-line treatment for advanced lung adenocarcinoma [3,4,5]. Despite substantial achievements in clinical care, a considerable proportion of patients does not derive benefit from anti-PD1/PD-L1 treatment. Accumulating evidence has proved that patients with EGFR mutations cannot benefit from immunotherapy [6,7,8]. The PD-L1 expression level, tumor mutation burden (TMB), and infiltrated lymphocyte have been identified as predictive markers for anti-PD1/PD-L1 immunotherapy [9]. Still, no report could give us a satisfying answer

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